New route to 15-hydroxydehydroabietic acid derivatives: Application to the first synthesis of some bioactive abietane and nor-abietane type terpenoids

Article abstract of DOI:10.1016/j.tetlet.2006.02.037

A new route to 15-hydroxydehydroabietic acid derivatives from abietic acid (11), via abieta-8,13(15)-dien-18-oic acid (12), is reported. Utilizing this, the first synthesis of bioactive terpenes 3, 6, 9 and 10, as well as natural diol 4 and lactones 7-8 was achieved.

Full text of DOI:10.1016/j.tetlet.2006.02.037

Tetrahedron Letters 47 (2006) 2577–2580
New route to 15-hydroxydehydroabietic acid derivatives:
application to the first synthesis of some bioactive abietane
and nor-abietane type terpenoids
E. J. Alvarez-Manzaneda,a,* R. Chahboun,a J. J. Guardia,a M. Lachkar,b
A. Dahdouh,a A. Laraa and I. Messourib
aDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Instituto de Biotecnologı´a, Universidad de Granada,
18071 Granada, Spain
bLaboratoire d’Ingenierie des Materiaux Organometalliques et Moleculaires, Faculte´ des Sciences,
`
Universite´ Sidi Mohammed Ben Abdellah, BP 1786 (Atlas), 30000 Fes, Morocco
Received 30 November 2005; revised 6 February 2006; accepted 7 February 2006
Available online 28 February 2006
Abstract—A new route to 15-hydroxydehydroabietic acid derivatives from abietic acid (11), via abieta-8,13(15)-dien-18-oic acid
(12), is reported. Utilizing this, the first synthesis of bioactive terpenes 3, 6, 9 and 10, as well as natural diol 4 and lactones 7–8
was achieved.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Abietane-type diterpenes constitute a group of second-
ary metabolites that are widespread in the vegetable
kingdom. Recent years have seen growing interest in this
class of substances after the isolation of a large variety
of compounds, mainly oxidized derivatives that present
various biological activities, for example, antitumour,1
antibiotic,2 antiviral,3 anti-inflammatory,4 immunosup-
pressive,5 antioxidant6 and antiparasitic,7 among others.
Moreover, many abietane terpenoids have long been
applied in various fields.8 Recently, some dehydroabietic
acid derivatives have been described as a novel scaffold
for large-conductance calcium-activated K+ channels.9
Continuing our research on the synthesis of bioactive
terpenoids,10 we have focused on the preparation of
15-hydroxydehydroabietic acid derivatives. Compounds
3, 6 and 8 are representative examples, due to their bio-
logical activity or structural features. Diol 311 and keto-
ester 612 show potent inhibitory effects on Epstein-Barr
virus early antigen (EBV-EA) activation induced by
the tumour promoter 12-O-tetradecanoylphorbol 13-
acetate. Picealactone B (8), a recently isolated diterpene,
contains a rare 5-dehydro-18,6-olide functionality.13
These 15-hydroxydehydroabietic acid derivatives are
also suitable intermediates to synthesize the corresponding
OH
OH
R
OH
O
O
COOR
R
R
O
O
1 R: COOH
2 R: COOMe
3 R: CH2OH
4 R: OH
5 R: H
6 R: Me
9
R: COOH
7 R: H
8 R: OH
10 R: Me
Keywords: Abietane diterpenes; Enantiospecific synthesis; Bioactive compounds; Oxidation; Selenium dioxide.
*
Corresponding author. Tel./fax: +34 958 24 80 89; e-mail: eamr@ugr.es
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.037

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E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 47 (2006) 2577–2580
13-hydroxy-8,11,13-podocarpatriene derivatives, such as
9, a highly fungistatic nor-abietane type terpenoid,14 and
10, an antioxidant metabolite isolated from Taiwania
cryptomerioides.15
the behaviour of methyl ester 13 under different oxida-
tion conditions. In most cases, the simultaneous oxida-
tion on C-7 and C-15 took place; only two oxidant
reagents among those essayed prevented the C-7 oxida-
tion. Photooxidation of 13 led to a complex mixture of
hydroperoxides (14,21,24 1524 and 16). Methyl 15-
hydroxydehydroabietate (2)24 was smoothly obtained
in quantitative yield when 13 was refluxed with selenium
dioxide in dioxane (Scheme 1).
Some chemical procedures to achieve 15-hydroxyde-
hydroabietic acid derivatives have been reported previ-
ously. The direct oxidation of dehydroabietic acid
involves the simultaneous reaction on C-7 and C-15,
affording the corresponding 15-hydroxy-7-oxodehydr-
oabietic acid (5) derivatives.16 15-hydroxydehydroabietic
acid (1) was obtained in only 10% by hydroperoxidation
of dehydroabietic acid and further reduction.17 Methyl
15-hydroxydehydroabietate (2) was synthesized from
methyl dehydroabietate in a two-step sequence involving
the oxymercuration–demercuration of the correspond-
ing dehydroisopropyl derivative; the main drawback of
this procedure is the low yield besides the obtention of
significative amounts of D6-derivatives, which compli-
cate the purification.18 Some examples of biotransfor-
mations have also been reported for hydroxylation on
the C-15 of dehydroabietic acid, even though the yields
achieved are always very low.19
Scheme 2 shows the first synthesis of bioactive diol 311
and abietanediol 422 from the 15-hydroxyderivative 2.
Compound 4 was obtained by saponification of the for-
mate, which results from the Baeyer–Villiger oxidation
of aldehyde 17.23
Bioactive ketoester 6 and picealactone B (8), an abie-
tane-type diterpene recently isolated from Picea morri-
sonicola,13 have also been prepared from 2 (Scheme 3).
The elaboration of enol-lactone 8 was previously inves-
tigated on methyl dehydroabietate (18). When an
oxygen stream was bubbled through a solution of 7-oxo-
derivative 19 in tert-butanol, in the presence of potas-
sium tert-butoxide, a 1:2 mixture of lactone 7 and
diosphenol 2024 was obtained. Compound 7, which
was easily separated from 20 after column chromatogra-
phy, has the same spectroscopic properties reported for
picealactone A, also isolated from P. morrisonicola.13
Abieta-8,13(15)-dien-18-oic acid (12), which is easily
prepared from abietic acid (11),20 could be a suitable
intermediate to synthesize 15-hydroxyderivatives of
abietane-type diterpenes. That is why we have studied
OH
(i)
(iv)
COOH
COOR
COOMe
12 R: H
13 R: Me
11
2
(ii)
(iii)
OOH
OOH
O
OOH
O
+
+
COOMe
COOMe
COOMe
15 (25%)
16 (20%)
14 (30%)
Scheme 1. Reagents and conditions: (i) Ref. 20, four steps, 59%; (ii) MeI, acetone, reflux, 12 h (95%); (iii) O2, MeOH, hm (200 W), 0 ꢁC, 3 h; (iv) SeO2,
dioxane, reflux, 30 min (quant.).
OH
(iii)
OH
(ii)
OH
(i)
2
CHO
17
CH2OH
OH
4
3
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, rt, 12 h (95%); (ii) PCC, CH2Cl2, rt, 45 min (75%); (iii) MCPBA, NaHCO3, CH2Cl2, reflux,
3 h; KOH, MeOH, reflux, 1 h (90%).

E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 47 (2006) 2577–2580
2579
(iii) or (iv)
R
R
R
R
(i)
(ii)
+
O
O
O
HOOC
O
COOMe
COOMe
OH
O
18 R: H
19 R: H
20 R: H
21 R: OH
7 R: H
8 R: OH
2
R:OH
6 R: OH
(v)
Scheme 3. Reagents and conditions: (i) PCC, AcONa, CH2Cl2, reflux, 4 h (19, 73%; 6, 65%); (ii) O2, t-BuOK, t-BuOH, rt, 2 h (7, 20, 96%; 8, 21,
98%); (iii) Amberlyst A-15, THF, 40 ꢁC, 4 h (95%); (iv) DCC, THF, rt, 90 min (97%); (v) 2 N KOH–MeOH, rt, 3 h; 2 N HCl, 0 ꢁC (81%).
OH
OH
OH
(iii-iv)
(i)
(vi)
2
COOR
R
10
22 R: Me
17 R: CHO
23 R: CH3
(ii)
(v)
9
R: H
Scheme 4. Reagents and conditions: (i) H2O2, BF3ÆOEt2, CH2Cl2, rt, 45 min (95%); (ii) KOH, MeOH, reflux, 1 h (90%); (iii) LiAlH4, THF, reflux,
12 h (95%); (iv) PCC, CH2Cl2, rt, 45 min (75%); (v) N2H4ÆH2O, triethylene glycol, reflux, 4 h (75%); (vi) H2O2, BF3ÆOEt2, CH2Cl2, rt, 1 h (97%).
5924; (b) Gao, J.; Han, G. Phytochemistry 1997, 44, 759–
763; (c) Kofujita, H.; Ota, M.; Taakahashi, K.; Kawai, Y.;
Hayashi, Y. Phytochemistry 2002, 61, 895–898; (d) Kup-
chan, S. M.; Schubert, R. M. Science 1974, 185, 791–793;
(e) Lee, K. Y.; Chang, W.-T.; Qiu, D.-M.; Kao, P. N.;
Rosen, G. D. J. Biol. Chem. 1999, 274, 13451–13455; (f)
US patent 2004063788, April 1, 2004; (g) World patent
9218119, October 29, 1992.
Under the same reaction conditions, the 15-hydroxy-
derivative 6 afforded an unresolvable 1:1 mixture of
lactone 8 and diosphenol 2124, which were characterized
after chemical interconversion. Treatment of the mix-
ture with amberlite A-15 or DCC in THF gave 8 as
the only product; alternatively, the treatment of lactone
8 with KOH in MeOH and further acidification yielded
21.
2. (a) Dellar, J. E.; Cole, M. D.; Waterman, P. G.
Phytochemistry 1996, 41, 735–738; (b) Ulubelen, A.;
Sonmez, U.; Topcu, G.; Bozok-Johansson, C. Phytochem-
istry 1996, 42, 145–147; (c) Ulubelen, A.; Topcu, G.; Eris,
C.; Sonmez, U.; Kartal, M.; Kurucu, S.; Bozok-Johans-
son, C. Phytochemistry 1994, 36, 971–974; (d) Moujir, L.;
Methyl 15-hydroxydehydroabietate (2) has also been
efficiently converted into the bioactive phenol 9, by
treating with hydrogen peroxide and boron trifluoride
etherate in dichloromethane and subsequent saponifica-
tion. In a similar way, the natural phenol 10 was synthe-
sized from 2, after reduction of the methoxycarbonyl
group (Scheme 4).
´
Gutierrez-Navarro, A. M.; San Andres, L.; Luis, J. G.
Phytochemistry 1993, 34, 1493–1496.
3. (a) Tada, M.; Chiba, K.; Okuno, K.; Ohnishi, E.; Yoshii,
T. Phytochemistry 1994, 35, 539–542; (b) Batista, O.;
Simoes, M. F.; Duarte, A.; Valdivia, M. L.; De La Torre,
M. C.; Rodriguez, B. Phytochemistry 1995, 38, 167–169.
4. (a) Shishido, K.; Got, K.; Miyoshi, S.; Takaishi, Y.;
Shibuya, M. J. Org. Chem. 1994, 59, 406–414; (b) Zheng,
Y.-L.; Lin, J.-F.; Lin, C.-C.; Xu, Y. Acta Pharm. Sin.
1994, 15, 540–543; (c) Zheng, J.-R.; Gu, K.-X.; Xu, L. F.;
Gao, J.-W.; Yu, Y.-H.; Tang, M.-Y. Acta Acad. Med. Sin.
1991, 13, 391–394.
In summary, a new route from abietic acid (11) to
15-hydroxydehydroabietic acid derivatives is reported.
Utilizing this, the first synthesis of natural terpenoids
3, 4, 6, 8–10 has been achieved, which allows to confirm
the assigned structures for these compounds.24
5. (a) Gu, W.-Z.; Chen, R.; Brandwein, S.; McAlpine, J.;
Burres, N. Int. J. Immunopharmacol. 1995, 17, 351–356;
(b) Yang, S.-X.; Gao, H.-L.; Xie, S.-S.; Zhang, W.-R.;
Long, Z.-Z. Int. J. Immunopharmacol. 1992, 14, 963; (c)
Qiu, D.-M.; Zhao, G.-H.; Aoki, Y.; Shi, L.-F.; Uyei, A.;
Nazarian, S.; Ng, J. C.-H.; Kao, P. N. J. Biol. Chem. 1999,
274, 13443–13450.
Acknowledgements
Financial support was received from Ministerio de Cien-
cia y Tecnologıa (Project PPQ 2002-03308) and from
Junta de Andalucia.
´
6. Nakatani, N.; Iwatani, R. Agric. Biol. Chem. 1984, 48,
2081–2084.
References and notes
7. Tan, N.; Kaloga, M.; Radtke, O. A.; Kiderlen, A. F.;
Oksuz, S.; Ulubelen, A.; Kolodziej, H. Phytochemistry
2002, 61, 881–884.
1. (a) Kupchan, S. M.; Karim, A.; Marcks, C. J. Org. Chem.
1969, 34, 3912–3918; J. Am. Chem. Soc. 1968, 90, 5923–

2580
E. J. Alvarez-Manzaneda et al. / Tetrahedron Letters 47 (2006) 2577–2580
8. (a) JP patent 2005132768, May 26, 2005; (b) EP 714786,
1H), 7.23 (d, J = 8.3 Hz, 1H). 13C NMR (CDCl3,
75 MHz): d 179.1 (C-18), 147.9 (C-9), 146.1 (C-13), 134.7
(C-8), 124.9 (C-14), 124.1 (C-11), 122.0 (C-12), 72.2 (C-
15), 51.9 (COOCH3), 47.6 (C-4), 44.8 (C-5), 38.0 (C-3),
37.0 (C-10), 36.7 (C-1), 31.6 (C-16 and C-17), 24.8 (C-18),
21.7 (C-2), 18.6 (C-6), 30.1 (C-7), 16.5 (C-20).
June 5, 1996; (c) EP 394793, October 31, 1990; (d) JP
patent 60001112, January 7, 1985.
9. Ohwada, T.; Nonomura, T.; Maki, K.; Sakamoto, K.;
Ohya, S.; Muraki, K.; Imaizumi, Y. Bioorg. Med. Chem.
Lett. 2003, 13, 3971–3974.
10. (a) Alvarez-Manzaneda, E. J.; Chahboun, R.; Bentaleb,
F.; Cabrera Torres, E.; Alvarez, E.; Haidour, A.; Ramos,
J. M.; Alvarez-Manzaneda, R.; El Houssame, S. Synlett
2004, 2701–2704; (b) Alvarez-Manzaneda, E. J.; Chah-
25
Compound 3: ½aꢀD ꢁ9.8 (c 1.1, CHCl3) [lit.11 [a]D ꢁ12.0 (c
0.82, CHCl3).
25
26
Compound 4: ½aꢀD ꢁ11.2 (c 0.9, CHCl3) [lit.22 ½aꢀD ꢁ13.0 (c
0.32, CHCl3).
25
´
boun, R.; Barranco Perez, I.; Cabrera, E.; Alvarez, E.;
Compound 6: ½aꢀD +7.9 (c 1.0, CHCl3) [not reported
Alvarez-Manzaneda, R. Tetrahedron Lett. 2005, 46, 5321–
5324.
previously].
25
19
Compound 8: ½aꢀD +19.8 (c 0.8, CHCl3) [lit.13 ½aꢀD +23.5 (c
11. Minami, J.; Wada, S.-I.; Tokuda, H.; Tanabe, G.;
Muraoka, O.; Tanaka, R. J. Nat. Prod. 2002, 65, 1921–
1923.
12. Kinouchi, Y.; Ohtsu, H.; Tokuda, H.; Nishino, H.;
Matsunaga, S.; Tanaka, R. J. Nat. Prod. 2000, 63, 817–
820.
0.25, CHCl3).
25
Compound 9: ½aꢀD +12.4 (c 0.9, CHCl3) [not reported
previously].
25
21
Compound 10: ½aꢀD +18.1 (c 1.0, CHCl3) [lit.15 ½aꢀD +16.7
(c 0.43, CHCl3).
Compound 14: 1H NMR (CDCl3, 300 MHz): d 1.07 (s,
3H), 1.16 (s, 3H), 1.26 (s, 6H), 2.09 (d, J = 8.8 Hz, 1H),
2.13 (d, J = 8.8 Hz, 1H), 2.38 (dd, J = 12.0, 7.2 Hz, 1H),
2.48 (m, 1H), 3.68 (s, 3H), 6.28 (br s, 1H). 13C NMR
(CDCl3, 75 MHz): d 178.5 (C-18), 144.4 (C-8), 126.2 (C-
14), 81.5 (C-13), 81.0 (C-9), 72.4 (C-15), 52.0 (COOCH3),
51.6 (C-5), 46.7 (C-4),39.1 (C-10), 38.2 (C-3), 30.9 (C-1),
25.3 (C-16), 24.8 (C-17), 24.2 (C-7), 24.0 (C-12), 21.8 (C-
11), 19.8 (C-6), 19.2 (C-19), 17.8 (C-20), 17.5 (C-2).
Compound 15: 1H NMR (CDCl3, 300 MHz): d 0.99 (s,
3H), 1.00 (s, 3H), 1.18 (s, 6H), 1.78 (br s, 3H), 1.79 (br s,
3H), 3.64 (s, 6H), 4.80 (t, J = 1.6 Hz, 1H), 4.83 (t,
J = 1.6 Hz, 1H), 4.85 (br s, 1H), 5.01 (br s, 1H). 13C
NMR (CDCl3, 75 MHz): d 179.3 (2 · C), 150.8 (C), 148.6
(C), 136.9 (C), 136.8 (C), 124.3 (C), 123.5 (C), 110.5 (CH2),
109.3 (CH2), 72.9 (C), 72.3 (C), 51.9 (2 · CH3), 47.7
(2 · C), 46.3 (CH), 46.1 (CH), 42.9 (CH2), 42.0 (CH2), 37.3
(C), 37.2 (C), 36.7 (CH2), 36.6 (CH2), 36.0 (CH2), 35.5
(CH2), 32.8 (CH2), 32.4 (CH2), 31.7 (2 · CH2), 21.5 (CH2),
21.4 (CH2), 21.1 (CH2), 20.2 (CH2), 20.1 (CH3), 19.5
(CH3), 18.8 (CH3), 18.4 (CH3), 18.2 (CH2), 16.5 (2 · CH3).
Compound 20: 1H NMR (CDCl3, 400 MHz): d 1.28 (d,
J = 6.8 Hz, 6H), 1.53 (s, 3H), 1.63 (s, 3H), 2.40 (br d,
J = 13.2 Hz, 1H), 2.94 (h, J = 6.8 Hz, 1H), 6.91 (br s, 1H),
7.43 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 7.47 (s,
2H), 8.03 (s, 1H). 13C NMR (CDCl3, 100 MHz): d 182.5
(C-18), 180.2 (C-7), 151.7 (C-9), 143.8 (C-5), 136.3 (C-13),
132.0 (C-12), 127.7 (C-8), 124.9 (C-11), 124.3 (C-14), 45.9
(C-4), 39.3 (C-10), 35.7 (C-20), 33.7 (C-15), 34.8 (C-1),
34.0 (C-3), 23.8 (C-16 and C-17), 22.0 (C-19), 17.6 (C-2).
Compound 21: 1H NMR (CD3COCD3, 400 MHz): d 1.50–
1.60 (m, 3H), 1.54 (m, 9H), 1.59 (s, 3H), 1.95 (m, 2H), 2.55
(m, 1H), 3.90 (br s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.83 (dd,
J = 84, 2.2 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H). 13C NMR
(CD3COCD3, 100 MHz): d 180.6 (C-18), 177.8 (C-7),
152.7 (C-9), 149.6 (C-13), 145.1 (C-5), 137.6 (C-6), 130.7
(C-12), 128.5 (C-8), 125.6 (C-11), 122.7 (C-14), 71.8 (C-
15), 46.3 (C-4), 40.0 (C-10), 36.6 (C-1), 36.0 (C-20), 35.6
(C-3), 32.0 (C-16 and C-17), 21.4 (CH3), 18.2 (C-2).
13. Kuo, Y.-H.; Yeh, M.-H.; Lin, H.-C. Chem. Pharm. Bull.
2004, 52, 861–863.
14. (a) Cheung, H. T. A.; Miyase, T.; Lenguyen, M. P.; Smal,
M. A. Tetrahedron 1993, 49, 7903–7915; (b) Franich, R.
A.; Gadgil, P. D.; Shain, L. Physiol. Plant Pathol. 1983,
23, 183–195.
15. Kuo, Y. H.; Chang, C. I.; Lee, C. K. Chem. Pharm. Bull.
2000, 48, 597–599.
16. (a) Takashi, M.; Sachiniko, I.; Yasuhiro, S.; Takashi, Y.
Bull. Chem. Soc. Jpn. 1988, 61, 723–727; (b) Li, W.-S.;
McChesney, J. D. J. Pharm. Sci. 1992, 81, 646–651.
17. JP patent 2003081940, March 19, 2003.
18. (a) Shao, L. P.; Gafvert, E.; Nilsson, U.; Karlberg, A. T.;
Nilsson, J. L. G. Phytochemistry 1995, 38, 853–857; (b)
´
Abad, A.; Agullo, C.; Arno, M.; Domingo, R. L.;
´
Zaragoza, R. J. J. Org. Chem. 1988, 53, 3761–3765.
19. (a) Kutney, J. P.; Choi, L. S. L.; Hewitt, G. M.; Salisbury,
P. J.; Singh, M. Appl. Environ. Microbiol. 1985, 47, 96–
100; (b) Ekman, R.; Sjoholm, R. Acta Chem. Scand. 1979,
B33, 76–78.
20. Abad, A.; Arno, M.; Domingo, L. R.; Zaragoza, R. J.
Tetrahedron 1985, 41, 4937–4940.
21. For related compounds see: Sy, L. K.; Brown, G. D. J.
Nat. Prod. 1998, 61, 907–912.
22. Ohtsu, H.; Tanaka, R.; Matsunaga, S. J. Nat. Prod. 1998,
61, 406–408.
23. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Alvarez-Man-
zaneda, R.; Chahboun, R.; Meneses, R.; Aparicio, M.
Synlett 1999, 713–716.
24. Spectroscopic properties of natural terpenoids (3, 4, 6, 8–
10) were identical to those reported in the literature. All
new compounds were fully characterized spectroscopically
and had satisfactory high resolution mass spectroscopy
data. Selected data:
Compound 2: 1H NMR (CDCl3, 300 MHz): d 1.20 (s, 3H),
1.27 (s, 3H), 1.54 (s, 6H), 1.96 (br s, 1H), 2.22 (dd,
J = 12.5, 2.2 Hz, 1H), 2.30 (br d, J = 11.9 Hz, 1H), 2.90
(m, 2H), 3.65 (s, 3H), 7.15 (br s, 1H), 7.20 (d, J = 8.3 Hz,